Type II diabetes is the most common form of diabetes accounting for 90% of diabetes cases. Over 100 million people worldwide have type-2 diabetes (nearly 17 million in the U.S.) and the prevalence is increasing dramatically in both the developed and developing worlds. Type-II diabetes is a lifelong illness, which generally starts in middle age or later part of life, but can start at any age. Patients with type-2 diabetes do not respond properly to insulin, the hormone that normally allows the body to convert blood glucose into energy or store it in cells to be used later. The problem in type-2 diabetes is a condition called insulin resistance where the body produces insulin, in normal or even high amounts, but certain mechanisms prevent insulin from moving glucose into cells. Because the body does not use insulin properly, glucose rises to unsafe levels in the blood, the condition known as hyperglycemia.
Over time, sustained hyperglycemia leads to glucotoxicity, which worsens insulin resistance and contributes to dysfunction in the beta cells of the pancreas. The degree of sustained hyperglycemia is directly related to diabetic microvascular complications and may also contribute to macrovascular complications. In this way, hyperglycemia perpetuates a cycle of deleterious effects that exacerbate type 2 diabetes control and complications.
It is now widely accepted that glycemic control makes a difference in type II diabetes patients. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications associated with elevated glucose in the blood. Oral therapeutic options for the treatment of type II diabetes mellitus include compounds known as: sulfonylureas, biguanides (metformin), thiazolidinediones, and alpha-glucosidase inhibitors. The active agents from each class are generally administered to patients alone. However, once monotherapy becomes inadequate, combination therapy is an attractive and rational course of action for treating hyperglycemia despite the known side effect of weight gain associated with sulfonylurea and thiazolidinone therapies.
Recently, a new class of anti-diabetics was discovered known as sodium-glucose transporter-2 inhibitors (SGLT2). SGLT2 inhibitors prevent the reabsorption of glucose into blood by the kidney. The kidney continuously filters glucose through the glomerulus into the bladder, however, nearly all of this glucose is reabsorbed. SGLT2 is the protein responsible for the majority of glucose reabsorption and helps the body retain glucose for its energy requirements. For patients with diabetes, retention of excess glucose by this pathway contributes to persistent hyperglycemia. Suppressing the activity of SGLT2 inhibits renal-glucose reabsorption in the body, thereby leading to the excretion of glucose in the urine.
Accordingly, the present invention provides bilayer tablet formulations that consist of metformin and an SGLT2 inhibitor for oral administration in the treatment of diseases or disorders associated with SGLT2 activity without weight gain associated with other therapies. The first layer of the bilayer tablet is metformin extended release (XR) or metformin XR in a reduced mass formulation. The second layer is an SGLT2 inhibitor formulation. The metformin/SGLT2 bilayer tablet of the present invention provides an antidiabetic therapy to patients that is both convenient and effective for controlling blood glucose levels.